Role of the intercalated disc in cardiac propagation and arrhythmogenesis

This review article discusses mechanisms underlying impulse propagation in cardiac muscle with specific emphasis on the role of the cardiac cell-to-cell junction, called the “intercalated disc.”The first part of this review deals with the role of gap junction channels, formed by connexin proteins, as a determinant of impulse propagation. It is shown that, depending on the underlying structure of the cellular network, decreasing the conductance of gap junction channels (so-called “electrical uncoupling”) may either only slow, or additionally stabilize propagation and reverse unidirectional propagation block to bidirectional propagation. This is because the safety factor for propagation increases with decreasing intercellular electrical conductance. The role of heterogeneous connexin expression, which may be present in disease states, is also discussed. The hypothesis that so-called ephaptic impulse transmission plays a role in heart and can substitute for electrical coupling has been revived recently. Whereas ephaptic transmission can be demonstrated in theoretical simulations, direct experimental evidence has not yet been presented. The second part of this review deals with the interaction of three protein complexes at the intercalated disc: (1) desmosomal and adherens junction proteins, (2) ion channel proteins, and (3) gap junction channels consisting of connexins. Recent work has revealed multiple interactions between these three protein complexes which occur, at least in part, at the level of protein trafficking. Such interactions are likely to play an important role in the pathogenesis of arrhythmogenic cardiomyopathy, and may reveal new therapeutic concepts and targets

Carotid atherosclerotic plaque segmentation in multi-weighted MRI using a two-stage neural network: Advantages of training with high-resolution imaging and histology

INTRODUCTION: A reliable and automated method to segment and classify carotid artery atherosclerotic plaque components is needed to efficiently analyze multi-weighted magnetic resonance (MR) images to allow their integration into patient risk assessment for ischemic stroke. Certain plaque components such as lipid-rich necrotic core (LRNC) with hemorrhage suggest a greater likelihood of plaque rupture and stroke event. Assessment for presence and extent of LRNC could assist in directing treatment with impact upon patient outcomes. METHODS: To address the need to accurately determine the presence and extent of plaque components on carotid plaque MRI, we proposed a two-staged deep-learning-based approach that consists of a convolutional neural network (CNN), followed by a Bayesian neural network (BNN). The rationale for the two-stage network approach is to account for the class imbalance of vessel wall and background by providing an attention mask to the BNN. A unique feature of the network training was to use ground truth defined by both high-resolution RESULTS: Our results show that the proposed method yielded accurate segmentation of carotid atherosclerotic plaque and outperforms not only manual segmentation by trained readers, who did not have access to the ex vivo or histopathology data, but also three state-of-the-art deep-learning-based segmentation methods. Further, the proposed approach outperformed a strategy where the ground truth was generated without access to the high resolution ex vivo MRI and histopathology. The accurate performance of this method was also observed in the additional 23-patient dataset from a different scanner. CONCLUSION: In conclusion, the proposed method provides a mechanism to perform accurate segmentation of the carotid atherosclerotic plaque in multi-weighted MRI. Further, our study shows the advantages of using high-resolution imaging and histology to define ground truth for training deep-learning-based segmentation methods

Mechanisms of Impaired Exercise Capacity in Short Duration Experimental Hyperthyroidism

Abstract To investigate the mechanism of reduced exercise tolerance in hyperthyroidism, we characterized cardiovascular function and determinants of skeletal muscle metabolism in 18 healthy subjects aged 26±1 yr (mean±SE) before and after 2 wk of daily ingestion of 100 pg of triiodothyronine (T3). Resting oxygen uptake, heart rate, and cardiac output increased and heart rate and cardiac output at the same submaximal exercise intensity were higher in the hyperthyroid state (P < 0.05). However, maximal oxygen uptake decreased after T3 administration (3.08±0.17 vs. 2.94±0.19 l/min; P < 0.001) despite increased heart rate and cardiac output at maximal exercise (P < 0.05). Plasma lactic acid concentration at an equivalent submaximal exercise intensity was elevated 25% (P < 0.01) and the arteriovenous oxygen difference at maximal effort was reduced (P < 0.05) in the hyperthyroid state. These effects were associated with a 21-37% decline in activities of oxidative (P < 0.001) and glycolytic (P < 0.05) enzymes in skeletal muscle and a 15% decrease in type 11A muscle fiber cross-sectional area (P < 0.05). Lean body mass was reduced (P < 0.001) and the rates of whole body leucine oxidation and protein breakdown were enhanced (P < 0.05). Thus, exercise tolerance is impaired in short duration hyperthyroidism because of decreased skeletal muscle mass and oxidative capacity related to accelerated protein catabolism but cardiac pump function is not reduced. (J. Clin

Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations

Aims: Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood. Methods and results: We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG. Conclusion: Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients